This invention relates to novel compounds and, more particularly, to novel derivatives of fatty acid analogs that have from one to three heteroatoms in the fatty acid moiety which can be oxygen, sulfur or nitrogen, and in which the carboxy-terminus has been modified to form, e.g., various amides, esters, ketones, alcohols, alcohol esters and nitriles thereof.
These novel compounds are useful as anti-viral and anti-fungal agents or pro-drugs of such agents and are particularly useful as inhibitors of retroviruses, especially lentiviruses such as the human immunodeficiency virus (HIV).
The fatty acid acylation of specific eukaryotic proteins is a well-established process. See, e.g., the review article by Towler et al., Ann. Rev. Biochem. 57, 69-99 (1988), and references cited therein.
Fatty acid analogs containing heteroatom replacements of methylene groups in the fatty acid chain by oxygen, sulfur and nitrogen have been shown to have various anti-viral and antifungal activity. See, e.g.,
Bryant et al., Proc. Natl. Acad. Sci. USA 86, 8655-8659 (1989); PA1 Bryant and Ratner, Proc. Natl. Acad. Sci. USA 87, 523-527 (1991); PA1 Doering et al., Science 252, 1851-1854 (1991); PA1 Bryant et al., Proc. Natl. Acad. Sci. USA 88, 2055-2059 (1991); PA1 and Devadas et al., J. Biol. Chem. 267, 7224-7239 (1992). PA1 U.S. Pat. Nos. 5,073,571; 5,082,967; 5,151,445; PA1 and EPO published patent applications EP 327,523 and EP 480,901. PA1 A=H, N.sub.3, CN, SH, OH, tetrazolyl, triazoyl, PA1 B=O, NR.sub.8, S(O).sub.m, lower alkylene, PA1 C=O, NR.sub.8, S(O).sub.m, lower alkylene, PA1 Alk.sub.1 =lower alkylene, branched or unbranched, PA1 Alk.sub.2 =lower alkylene, branched or unbranched, PA1 Alk.sub.3 =lower alkylene, branched or unbranched or W substituted lower alkylene, PA1 Y=COCl, CONRR.sub.1, CO-AA-OR.sub.3, CONR.sub.2 -AA-OR.sub.3, CO.sub.2 R.sub.4, COR.sub.5, CN, CH.sub.2 OH, CSNH.sub.2, CH.sub.2 O.sub.2 CR6, ##STR2## and wherein m=0-2, PA1 W=OZ, halogen, NR.sub.8, alkyl, aryl, arylalkyl, PA1 Z=H, alkanoyl, aroyl, arylalkanoyl, PA1 R=H, alkyl, aryl, arylalkyl, PA1 R.sub.1 =H, alkyl, aryl, arylalkyl, PA1 R.sub.2 =H, alkyl, aryl, arylalkyl, PA1 R.sub.3 =H, alkyl, aryl, arylalkyl, PA1 R.sub.4 =H, alkyl, aryl, arylalkyl, PA1 R.sub.5 =alkyl, aryl, arylalkyl, PA1 R.sub.6 =alkyl, aryl, arylalkyl, PA1 R.sub.7 =H, alkyl, aryl, arylalkyl, and PA1 R.sub.9 =H, alkyl, aryl, arylalkyl, PA1 AA=D, L, DL or achiral amino acid side chain, and provided that when Y=CO.sub.2 R.sub.4, R.sub.4 is aryl or arylalkyl, and provided further that at least one of B or C contains a N, O or S heteroatom. PA1 When B and/or C are any of the heteroatoms O, S(O).sub.m and NR.sub.8, each of these heteroatoms replaces a methylene group in the fatty acid chain. PA1 A compound of Formula I in which PA1 A compound of Formula I in which PA1 A compound of Formula I in which PA1 (1) aliphatic side chains, PA1 (2) hydroxylic side chains, PA1 (3) carboxylic side chains and their amides, PA1 (4) basic side chains, PA1 (5) aromatic side chains, PA1 (6) sulfur-containing side chains, and PA1 (7) the imino acids. PA1 D-Alanine PA1 D-Isoleucine PA1 D-Phenylalanine PA1 D-Glutamic acid PA1 D-Lysine PA1 D-Tryptophan PA1 D-Threonine PA1 .beta.-Alanine (3-Aminopropionic acid) PA1 Homocystine (4,4'-Dithiobis2-amino-butanoic acid!) PA1 Norleucine (2-Aminohexanoic acid) PA1 Norvaline (2-Aminovaleric acid) PA1 Ornithine (2,5-Diaminopentanoic acid) PA1 Penicillamine (3-Mercapto-D-valine) PA1 Phenylglycine and N-Phenylglycine PA1 Sarcosine (N-Methylglycine) PA1 Taurine (2-Aminoethanesulfonic acid) PA1 f is zero or one; PA1 X is selected from the group consisting of OH, O-alkyl having from one to six carbon atoms, and N(R.sub.1)R in which R and R.sub.1 are H or alkyl having from one to six carbon atoms or arylalkyl having from one to eight carbon atoms; PA1 D is selected from the group consisting of H, alkyl, aryl, arylalkyl and carboxyalkyl; PA1 E is selected from the group consisting of H, alkyl, aryl, arylalkyl, heteroarylalkyl, arylalkyl substituted with OH or halogen, benzofused heteroarylalkyl, hydroxyalkyl, alkoxy- alkyl, arylalkoxyalkyl, thioalkyl, alkylthioalkyl, arylalkylthioalkyl, carboxyalkyl, carboxamidoalkyl, aminoalkyl, aminohydroxyalkyl, diaminoalkyl and guanidinoalkyl; PA1 and in which the number of carbon atoms in each of D and E is from zero to eight. PA1 H is illustrated in glycine; PA1 Alkyl is illustrated in alanine, isoleucine, leucine and valine; PA1 Aryl is illustrated in phenylglycine; PA1 Arylalkyl is illustrated in phenylalanine; PA1 Arylalkyl substituted with OH or halogen is illustrated in tyrosine and fluorophenylalanine; PA1 Heteroarylalkyl (including benzofused) is illustrated in histidine and tryptophane; PA1 Hydroxyalkyl is illustrated in serine and threonine; Alkoxyalkyl and arylalkoxyalkyl are illustrated in O-methylserine, O-benzylserine and O-benzylthreonine; PA1 Thioalkyl is illustrated in cysteine and its disulfide dimer cystine; PA1 Alkylthioalkyl and arylalkylthioalkyl are illustrated in methionine and S-benzylcysteine; PA1 Carboxyalkyl is illustrated in aspartic acid and glutamic acid; PA1 Carboxamidoalkyl is illustrated in glutamine and asparagine; PA1 Aminoalkyl is illustrated in lysine, N-(O-benzyl)-carbamoyllysine and N-(O-orthochlorobenzyl)-carbamoyllysine; PA1 Amino-hydroxyalkyl is illustrated in hydroxylysine; PA1 Diaminoalkyl is illustrated in aminolysine and ornithine; and PA1 Guanidinoalkyl is illustrated by arginine and N'-toluenesulfonylarginine. PA1 H is illustrated in glycine (Gly); PA1 Alkyl is illustrated in N-(CH.sub.3)-Gly-Aryl is illustrated in N-(Ph)-Gly; PA1 Arylalkyl is illustrated in N-(Bn)-Gly; and PA1 Carboxyalkyl is illustrated in N-(Gly-oEt)-Gly; PA1 Gly-OH, PA1 Gly-OEt, PA1 Gly-Ot-Bu, PA1 NH(CH.sub.2).sub.2 CO.sub.2 Et, PA1 Gly-Gly-OEt, PA1 N-(Gly-OEt)-Gly-OEt, PA1 N-(CH.sub.3)-Gly-OEt, PA1 N-(Ph)-Gly-OEt, PA1 N-(Bn)-Gly-OEt, PA1 (.+-.)-NHCH.sub.2 CH(CH.sub.3)CO.sub.2 Et, PA1 L-Ala-OEt, PA1 L-NHCH.sub.2 CH(CH.sub.3)CO.sub.2 Et, PA1 D-Ala-OEt, PA1 L-Ile-OEt, PA1 D-Ile-OEt, PA1 L-Phe-OH, PA1 NHCH.sub.2 CH(CH.sub.2 Bn)CO.sub.2 Et, PA1 L-Phe-OEt, PA1 L-Phe-O-t-Bu, PA1 D-Phe-OH, PA1 D-Phe-O-Et, PA1 D-Phe-O-t-Bu, PA1 L-Glu(OBzl)-OEt, PA1 D-Glu(OBzl)-OEt, PA1 D-Lys(Cl-Z)-OEt, PA1 L-Lys(CI-Z)-OEt, PA1 L-Trp-OEt, PA1 D-Trp-OEt, PA1 L-Thr(OBzl)-OEt, and PA1 D-Thr(OBzl)-OEt. PA1 and in which the number of carbon atoms in alkyl are from one to eight and the number of carbon atoms in aryl is six. PA1 X is selected from the group consisting of cyano, tetrazole, N-alkyltetrazole and N-arylalkyltetrazole; PA1 and in which the number of carbon atoms in alkyl is from one to eight, and the number of carbon atoms in aryl is six. PA1 CN, PA1 CONEt.sub.2, PA1 CONHCH.sub.2 Ph, PA1 CO-Gly-OEt, PA1 CO-D-Phe-OEt, and PA1 CO-L-Phe-OEt.
See also,
In French Patent application 2,657,259, N-myristoyl-(S)-phenylalanine is disclosed as an inhibitor of NMT for treatment of cancer and retroviral infection, e.g. AIDS. Antiviral myristoyl-glycine is disclosed in Japanese Patent applications 62-126384 and 62-255810. These reported myristoylamino acids do not contain heteroatoms in the myristic acid moiety.